Apparatus for reversal of myocardial remodeling with pre-excitation

ABSTRACT

An apparatus for reversing ventricular remodeling with electro-stimulatory therapy. A ventricle is paced by delivering one or more stimulatory pulses in a manner such that a stressed region of the myocardium is pre-excited relative to other regions in order to subject the stressed region to a lessened preload and afterload during systole. The unloading of the stressed myocardium over time effects reversal of undesirable ventricular remodeling.

CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.13/279,493, filed on Oct. 24, 2011, which is a continuation of U.S.patent application Ser. No. 12/484,882, filed on Jun. 15, 2009, nowissued as U.S. Pat. No. 8,046,066, which is a continuation of U.S.patent application Ser. No. 11/469,620, filed on Sep. 1, 2006, nowissued as U.S. Pat. No. 7,548,782, which is a continuation of U.S.patent application Ser. No. 10/649,468, filed on Aug. 27, 2003, nowissued as U.S. Pat. No. 7,103,410, which is a continuation of U.S.patent application Ser. No. 09/844,256, filed on Apr. 27, 2001, nowissued as U.S. Pat. No. 6,628,988, the specifications of which areincorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to apparatus and methods for electrostimulationof the heart including cardiac pacing with an artificial pacemaker. Inparticular, the invention relates to a method and apparatus forstimulating the heart in order to effect reversal of myocardialremodeling.

BACKGROUND

Congestive heart failure (CHF) is a clinical syndrome in which anabnormality of cardiac function causes cardiac output to fall below alevel adequate to meet the metabolic demand of peripheral tissues. CHFcan be due to a variety of etiologies with that due to ischemic heartdisease being the most common. Inadequate pumping of blood into thearterial system by the heart is sometimes referred to as “forwardfailure,” with “backward failure” referring to the resulting elevatedpressures in the lungs and systemic veins which lead to congestion.Backward failure is the natural consequence of forward failure as bloodin the pulmonary and venous systems fails to be pumped out. Forwardfailure can be caused by impaired contractility of the ventricles or byan increased afterload (i.e., the forces resisting ejection of blood)due to, for example, systemic hypertension or valvular dysfunction. Onephysiological compensatory mechanism that acts to increase cardiacoutput is due to backward failure which increases the diastolic fillingpressure of the ventricles and thereby increases the preload (i.e., thedegree to which the ventricles are stretched by the volume of blood inthe ventricles at the end of diastole). An increase in preload causes anincrease in stroke volume during systole, a phenomena known as theFrank-Starling principle. Thus, heart failure can be at least partiallycompensated by this mechanism but at the expense of possible pulmonaryand/or systemic congestion.

When the ventricles are stretched due to the increased preload over aperiod of time, the ventricles become dilated. The enlargement of theventricular volume causes increased ventricular wall stress at a givensystolic pressure. Along with the increased pressure-volume work done bythe ventricle, this acts as a stimulus for hypertrophy of theventricular myocardium which leads to alterations in cellular structure,a process referred to as ventricular remodeling. Hypertrophy canincrease systolic pressures but also decreases the compliance of theventricles and hence increases diastolic filling pressure to result ineven more congestion. It also has been shown that the sustained stressescausing hypertrophy may induce apoptosis (i.e., programmed cell death)of cardiac muscle cells and eventual wall thinning which causes furtherdeterioration in cardiac function. Thus, although ventricular dilationand hypertrophy may at first be compensatory and increase cardiacoutput, the process ultimately results in both systolic and diastolicdysfunction. It has been shown that the extent of ventricular remodelingis positively correlated with increased mortality in CHF patients. It iswith reversing such ventricular remodeling that the present invention isprimarily concerned.

SUMMARY OF THE INVENTION

The present invention relates to an apparatus and method for reversingventricular remodeling with electro-stimulatory therapy. In accordancewith the invention, a ventricle is paced by delivering one or morestimulatory pulses in a manner such that a previously stressed andremodeled region of the myocardium is pre-excited relative to otherregions in order to subject the region to a lessened preload andafterload during systole. By unloading the region in this way over aperiod of time, reversal of undesirable ventricular remodeling iseffected. Pre-excitation may also be applied to stressed regions of themyocardium that have been weakened by ischemia or other causes in orderto prevent further dilation and/or promote healing.

The ventricular stimulatory pulse or pulses may be delivered inaccordance with a programmed bradycardia pacing mode in response tosensed cardiac activity and lapsed time intervals. In one embodiment, astimulating/sensing electrode is disposed in the ventricle at a selectedsite in proximity to a stressed region. Pacing that pre-excites theventricle at this site results in the stressed region being excitedbefore other regions of the ventricular myocardium as the wave ofexcitation spreads from the paced site. Other embodiments involvemulti-site pacing in which a plurality of stimulating/sensing electrodesare disposed in the ventricles. Pacing the ventricles during a cardiaccycle then involves outputting pulses to the electrodes in a specifiedsequence. In accordance with the invention, the pulse output sequencemay be specified such that a stressed region of the ventricularmyocardium is excited before other regions as the wave of excitationspreads from the multiple pacing sites.

For example, in multi-site univentricular pacing, a plurality ofstimulating/sensing electrodes are provided for a single ventricle.Stimulatory pulses are then delivered through each electrode in aspecified pulse output sequence in order to pace the ventricle during acardiac cycle. In a pacemaker configured for biventricular pacingtherapy, stimulating/sensing electrodes are provided for both the leftand right ventricles such that the ventricles are then paced during acardiac cycle by the delivery of both right and left ventricularstimulatory pulses if not inhibited by intrinsic activity. The timing ofthe right and left ventricular stimulatory pulses may be specified by apulse output sequence that includes an interventricular delay intervaldefining in what order the ventricles are paced and the time delaybetween the paces. With either multi-site univentricular pacing orbiventricular pacing, the pulse output sequence can be specified so asto excite a stressed region of the myocardium earlier than other regionsby a pre-excitation time interval.

The pulse output sequence of a multi-site pacemaker may be initiallyspecified by a clinician in accordance with regional measurements ofmyocardial mass so that stressed regions are excited first during apaced cardiac cycle. In another embodiment, an implanted device mayautomatically adjust the pulse output sequence in accordance withmeasurements of conduction delays or impedance measurements that reflectregional variations in myocardial mass or intrinsic conduction sequence.

The pulse output sequence best suited for reversal of remodeling may notbe the optimum pulse output sequence for maximizing hemodynamicperformance. In another embodiment, therefore, the pulse output sequenceis adjusted automatically in accordance with activity level measurementsreflective of metabolic demand. The pulse output sequence is thenalternated between one designed to produce hemodynamically moreeffective contractions when metabolic needs of the body are great to onedesigned for remodeling reversal when metabolic needs are less.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of an exemplary cardiac rhythm managementdevice for practicing the present invention.

FIGS. 2A-B are diagrams showing exemplary placements of sensing/pacingelectrodes.

DETAILED DESCRIPTION

Conventional cardiac pacing with implanted pacemakers involvesexcitatory electrical stimulation of the heart by an electrode inelectrical contact with the myocardium. (As the term is used herein,“excitatory stimulation” refers to stimulation sufficient to causecontraction of muscle fibers, which is also commonly referred to aspacing. Furthermore, the term “pacemaker” should be taken to mean anycardiac rhythm management device with a pacing functionality, regardlessof any other functions it may perform such ascardioversion/defibrillation or drug delivery.) The pacemaker is usuallyimplanted subcutaneously on the patient's chest, and is connected to anelectrode for each paced heart chamber by leads threaded through thevessels of the upper venous system into the heart. In response to sensedelectrical cardiac events and elapsed time intervals, the pacemakerdelivers to the myocardium a depolarizing voltage pulse of sufficientmagnitude and duration to cause an action potential. A wave ofdepolarizing excitation then propagates through the myocardium,resulting in a heartbeat.

Some form of cardiac pacing can often benefit CHF patients. For example,sinus node dysfunction resulting in bradycardia can contribute to heartfailure which can be corrected with conventional bradycardia pacing.Also, some CHF patients suffer from some degree of AV block such thattheir cardiac output is improved by synchronizing atrial and ventricularcontractions with dual-chamber pacing using a programmed AV delay time(i.e., atrial triggered ventricular pacing or AV sequential pacing). CHFpatients may also suffer from conduction defects of the specializedconduction system of the heart (a.k.a. bundle branch blocks) so that adepolarization impulse from the AV node reaches one ventricle before theother. Stretching of the ventricular wall brought about by CHF can alsocause slowed conduction of depolarization impulses through theventricle. If conduction velocity is slowed in the left ventricle morethan the right, for example, the contraction of the two ventriclesduring ventricular systole becomes uncoordinated which lessens pumpingefficiency. In both of these situations, cardiac output can be increasedby improving the synchronization of right and left ventricularcontractions. Cardiac pacemakers have therefore been developed whichprovide pacing to both ventricles. (See, e.g., U.S. Pat. No. 4,928,688,issued to Mower and hereby incorporated by reference.)

The specialized His-Purkinje conduction network of the heart rapidlyconducts excitatory impulses from the sin θ-atrial node to theatrio-ventricular node, and thence to the ventricular myocardium toresult in a coordinated contraction of both ventricles. Artificialpacing with an electrode fixed into an area of the myocardium does nottake advantage of the heart's normal specialized conduction system forconducting excitation throughout the ventricles. This is because thespecialized conduction system can only be entered by impulses emanatingfrom the atrio-ventricular node. Thus the spread of excitation from aventricular pacing site must proceed only via the much slower conductingventricular muscle fibers, resulting in the part of the ventricularmyocardium stimulated by the pacing electrode contracting well beforeparts of the ventricle located more distally to the electrode. Althoughthe pumping efficiency of the heart is somewhat reduced from theoptimum, most patients can still maintain more than adequate cardiacoutput with artificial pacing.

In multi-site pacing, the atria or ventricles are paced at more than onesite in order to effect a spread of excitation that results in a morecoordinated contraction. Biventricular pacing, as described above, isone example of multi-site pacing in which both ventricles are paced inorder to synchronize their respective contractions. Multi-site pacingmay also be applied to only one chamber. For example, a ventricle may bepaced at multiple sites with excitatory stimulation pulses in order toproduce multiple waves of depolarization that emanate from the pacingsites. This may produce a more coordinated contraction of the ventricleand thereby compensate for intraventricular conduction defects that mayexist. Stimulating one or both ventricles with multi-site pacing inorder to improve the coordination of the contractions and overcomeinterventricular or intraventricular conduction defects is termedresynchronization therapy.

Altering the coordination of ventricular contractions with multi-sitepacing can also be used to deliberately change the distribution of wallstress experienced by the ventricle during the cardiac pumping cycle.The degree to which a heart muscle fiber is stretched before itcontracts is termed the preload. The maximum tension and velocity ofshortening of a muscle fiber increases with increasing preload. Theincrease in contractile response of the heart with increasing preload isknown as the Frank-Starling principle. When a myocardial regioncontracts late relative to other regions, the contraction of thoseopposing regions stretches the later contracting region and increasesthe preload. The degree of tension or stress on a heart muscle fiber asit contracts is termed the afterload. Because pressure within theventricles rises rapidly from a diastolic to a systolic value as bloodis pumped out into the aorta and pulmonary arteries, the part of theventricle that first contracts due to an excitatory stimulation pulsedoes so against a lower afterload than does a part of the ventriclecontracting later. Thus a myocardial region that contracts later thanother regions is subjected to both an increased preload and afterload.This situation is created frequently by the ventricular conductiondelays associated with heart failure and ventricular dysfunction.

The heart's initial physiological response to the uneven stressresulting from an increased preload and afterload is compensatoryhypertrophy in those later contracting regions of the myocardium. In thelater stages of remodeling, the regions may undergo atrophic changeswith wall thinning due to the increased stress. The parts of themyocardium that contract earlier in the cycle, on the other hand, aresubjected to less stress and are less likely to undergo hypertrophicremodeling. The present invention makes use of this phenomena in orderto effect reversal of remodeling by pacing one or more sites in aventricle (or an atrium) with one or more excitatory stimulation pulsesduring a cardiac cycle with a specified pulse output sequence. The paceor paces are delivered in a manner that excites a previously stressedand remodeled region of the myocardium earlier during systole so that itexperiences less afterload and preload. This pre-excitation of theremodeled region relative to other regions unloads the region frommechanical stress and allows reversal of remodeling to occur.

In another application of the invention, pre-excitation stimulation maybe used to unload a stressed myocardial region that has been weakened byischemia or other causes. Such regions of the myocardium may beparticularly vulnerable to dilation and formation of aneurysms. Anincreased preload and afterload also requires an increased energyexpenditure by the muscle which, in turn, increases its perfusionrequirements and may result in further ischemia. Pre-excitation of anischemic region may thus reduce the region's need for blood as well asreduce the mechanical stress to which the region is subjected duringsystole to reduce the likelihood of further dilation.

A block diagram of a cardiac rhythm management device suitable forpracticing the present invention is shown in FIG. 1. The controller ofthe device is made up of a microprocessor 10 communicating with a memory12 via a bidirectional data bus, where the memory 12 typically comprisesa ROM (read-only memory) for program storage and a RAM (random-accessmemory) for data storage. The controller could also include dedicatedcircuitry either instead of, or in addition to, the programmedmicroprocessor for controlling the operation of the device. The devicehas atrial sensing/stimulation channels comprising electrode 34, lead33, sensing amplifier 31, pulse generator 32, and an atrial channelinterface 30 which communicates bidirectionally with a port ofmicroprocessor 10. The device also has multiple ventricularsensing/stimulation channels for delivering multi-site univentricular orbiventricular pacing. Two such ventricular channels are shown in thefigure that include electrodes 24 a-b, leads 23 a-b, sensing amplifiers21 a-b, pulse generators 22 a-b, and ventricular channel interfaces 20a-b where “a” designates one ventricular channel and “b” designates theother. For each channel, the same lead and electrode may be used forboth sensing and stimulation. The channel interfaces 20 a-b and 30 mayinclude analog-to-digital converters for digitizing sensing signalinputs from the sensing amplifiers and registers which can be written toby the microprocessor in order to output stimulation pulses, change thestimulation pulse amplitude, and adjust the gain and threshold valuesfor the sensing amplifiers. A telemetry interface 40 is provided forcommunicating with an external programmer.

The controller is capable of operating the device in a number ofprogrammed pacing modes which define how pulses are output in responseto sensed events and expiration of time intervals. Most pacemakers fortreating bradycardia are programmed to operate synchronously in aso-called demand mode where sensed cardiac events occurring within adefined interval either trigger or inhibit a pacing pulse Inhibiteddemand pacing modes utilize escape intervals to control pacing inaccordance with sensed intrinsic activity such that a pacing pulse isdelivered to a heart chamber during a cardiac cycle only afterexpiration of a defined escape interval during which no intrinsic beatby the chamber is detected. Escape intervals for ventricular pacing canbe restarted by ventricular or atrial events, the latter allowing thepacing to track intrinsic atrial beats. Rate-adaptive pacing modes canalso be employed where the ventricular and/or atrial escape intervalsare modulated based upon measurements corresponding to the patient'sexertion level. As shown in FIG. 1, an activity level sensor 52 (e.g., aminute ventilation sensor or accelerometer) provides a measure ofexertion level to the controller for pacing the heart in a rate-adaptivemode. Multiple excitatory stimulation pulses can also be delivered tomultiple sites during a cardiac cycle in order to both pace the heart inaccordance with a bradycardia mode and provide resynchronization ofcontractions to compensate for conduction defects. In accordance withthe invention, the controller may also be programmed to deliverstimulation pulses in a specified pulse output sequence in order toeffect reduction of stress to a selected myocardial region.

The invention may be beneficially applied to unload a stressedmyocardial region that is either hypertrophied or thinned. FIG. 2Adepicts a left ventricle 200 with pacing sites 210 and 220 to which maybe fixed epicardial stimulation/sensing electrodes. The myocardium atpacing site 210 is shown as being hypertrophied as compared to themyocardium at pacing site 220. A cardiac rhythm management device suchas shown in FIG. 1 may deliver stimulation pulses to both sites inaccordance with a pacing mode through its ventricularstimulation/sensing channels. In order to unload the hypertrophied site210 during systole and thereby promote reversal of the hypertrophy, theventricle is paced with a pulse output sequence that stimulates thehypertrophied site 210 before the other site 220. The lessenedmechanical stress during systole then allows the site 210 to undergoreversal of the hypertrophy. FIG. 2B shows a left ventricle 200 in whichthe pacing site 240 is relatively normal while the site 230 is amyocardial region that has been thinned due to late state remodeling orother stresses such as ischemia. Again, pacing of the ventricle withpre-excitation stimulation of site 230 relative to the site 240 unloadsthe thinned region and subjects it to less mechanical stress duringsystole. The result is either reversal of the remodeling or reduction offurther wall thinning.

In one embodiment, a pre-excitation stimulation pulse is applied to astressed region either alone or in a timed relation to the delivery of astimulation pulse applied elsewhere to the myocardium. For example, boththe right and left ventricles can be paced at separate sites bystimulation pulses delivered with a specified interventricular delaybetween the pulses delivered to each ventricle. By adjusting theinterventricular delay so that one of the ventricular pacing sites ispre-excited relative to the other, the spread of activation between thetwo pacing sites can be modified to change the wall stresses developednear these sites during systolic contraction. Other embodiments mayemploy multiple electrodes and stimulation channels to deliver pulses tomultiple pacing sites located in either of the atria or the ventriclesin accordance with a specified pulse output sequence. A multi-sitepacemaker may also switch the output of pacing pulses between selectedelectrodes or groups of electrodes during different cardiac cycles.Pacing is then delivered to a heart chamber through a switchableconfiguration of pacing electrodes, wherein a pulse output configurationis defined as a specific subset of a plurality of electrodes fixed tothe paced chamber and to which pacing pulses are applied as well as thetiming relations between the pulses. A plurality of different pulseoutput configurations may be defined as subsets of electrodes that canbe selected for pacing. By switching the pulse output configuration to adifferent configuration, pacing to the heart chamber is therebytemporally distributed among the total number of fixed electrodes. Theprinciple remains the same in these embodiments, however, of unloading astressed myocardial site by pre-exciting it relative to other regions ofthe myocardium.

In other embodiments, a stressed region of the ventricular myocardium ispre-excited in a timed relation to a triggering event that indicates anintrinsic beat has either occurred or is imminent. For example, apre-excitation stimulation pulse may be applied to a stressed regionimmediately following the earliest detection of intrinsic activationelsewhere in the ventricle. Such activation may be detected from anelectrogram with a conventional ventricular sensing electrode. Anearlier occurring trigger event may be detected by extracting the Hisbundle conduction potential from a special ventricular sensing electrodeusing signal processing techniques.

In order to deliver a pre-excitation stimulus to a stressed site at atime well before any intrinsic activation takes place at other sites,the stimulus can be applied after a specified AV delay intervalfollowing an atrial sense or atrial pace. The objective in thissituation is to deliver the pre-excitation stimulus before theexcitation from the atrio-ventricular node reaches the ventricles viathe specialized conduction pathway. Accordingly, the normal intrinsicatrio-ventricular delay (e.g., the PR interval on an EKG or theequivalent electrogram interval recorded using implanted leads) can bemeasured, with the AV pacing delay interval then programmed to beshorter than the measured intrinsic AV delay interval by a specifiedpre-excitation interval. The AV pacing delay interval may be eitherfixed at some value (e.g., at 60 ms, with a variable range of 0-150 ms)or be made to vary dynamically with a measured variable such as heartrate or exertion level.

The AV pacing delay interval for delivering a pre-excitation stimulusfollowing an atrial sense or pace may also be set in accordance with ameasured intrinsic conduction delay interval between the site to bepre-excited and another ventricular site, referred to as a V-V interval.The objective in this case is to reverse the intrinsic conduction delayexisting between the two sites by pacing with a similar delay ofopposite sign. For example, the intrinsic conduction delay between astressed ventricular site and an earlier excited site is measured. Thestressed site is then pre-excited after an AV pacing delay intervalfollowing an atrial sense or pace that is set in accordance with themeasured V-V interval. In one embodiment, the pre-excitation interval isset as a linear function of the V-V interval:

Pre-excitation interval=(a)(V-V interval)+b

The AV pacing delay interval is then computed by subtracting thepre-excitation interval from the measured intrinsic AV delay interval.

A clinician may use various techniques in order to determine areas thathave undergone remodeling or are otherwise stressed. For example,ventricular wall thickness abnormalities and regional variations inmyocardial mass may be observed with echocardiography or magneticresonance imaging. Observation of akinetic or dyskinetic regions of theventricle during contraction with an appropriate imaging modality mayalso be used to indicate stressed regions. Coronary angiogramsindicating blood flow abnormalities and electrophysiological studiesindicating regions of ischemia or infarction may be used to identifyregions that have been stressed due to ischemia. Electrophysiologicalstudies may also be used to determine regional conduction delays thatcan be reversed with pre-excitation stimulation. The pulse outputsequence of a multi-site pacemaker or the interventricular delay of abiventricular pacemaker may then be initially specified in accordancewith those findings so that stressed regions are excited first during apaced cardiac cycle.

In a further refinement, an implanted cardiac rhythm management devicemay automatically adjust the pulse output sequence in accordance withmeasurements of myocardial mass. Such measurements may be made bymeasuring the conduction delays of excitation spreading through themyocardium as sensed by multiple sensing/stimulation electrodes.Increased conductions delays through a region, for example, may bereflective of stress in the region that can be reduced by pre-excitationstimulation. In another embodiment, impedance measurements may be madebetween electrodes in proximity to the heart that correlate withvariations in myocardial mass and contraction sequence. Suchmeasurements may be used to identify akinetic or dyskinetic regions ofthe myocardium as well as to indicate wall thickness abnormalities. Theparticular pre-excitation interval used by the device may also beautomatically adjusted in accordance with detected changes in theremodeling process. That is, the pre-excitation interval may beshortened as remodeling is reversed or increased as remodeling worsens.Remodeling changes can be detected by, for example, measuring changes ortrends in conduction delays, contraction sequences, end-diastolicvolume, stroke volume, ejection fraction, wall thickness, or pressuremeasurements.

In another embodiment, the pulse output sequence used by a cardiacrhythm management may be alternated between one designed to producehemodynamically more effective contractions when metabolic needs of thebody are great to one designed to promote reverse remodeling whenmetabolic needs are less. A pulse output sequence that unloads ahypertrophic region may not be the optimum pulse output sequence formaximizing hemodynamic performance. For example, a more hemodynamicallyeffective contraction may be obtained by exciting all areas of themyocardium simultaneously, which may not effectively promote reversal ofthe hypertrophy or remodeling. The pulse output sequence may thereforebe adjusted automatically in accordance with exertion level measurementsreflective of metabolic demand so that pulse output sequences thatunload hypertrophied or stressed regions are not used during periods ofincreased exertion.

Although the invention has been described in conjunction with theforegoing specific embodiments, many alternatives, variations, andmodifications will be apparent to those of ordinary skill in the art.Other such alternatives, variations, and modifications are intended tofall within the scope of the following appended claims.

What is claimed is:
 1. A cardiac pacing device, comprising: sensing andpulse generation circuitry for connecting to a first electrode disposedat a stressed first ventricular site and for connecting to a secondelectrode disposed at a second ventricular site that is excited earlierduring an intrinsic contraction; a controller for controlling thedelivery of pacing pulses; and, wherein the controller is programmed todeliver a pacing pulse to the first ventricular site during a cardiaccycle before excitation of the second ventricular site in order tosubject the stressed region to less mechanical stress when themyocardium contracts.
 2. The device of claim 1 further comprisingsensing circuitry for connecting to an atrial electrode and wherein thecontroller is programmed to deliver the pacing pulse to the firstventricular site after expiration of an AV delay interval triggered byan atrial sense.
 3. The device of claim 1 further comprising pacingcircuitry for connecting to an atrial electrode and wherein thecontroller is programmed to deliver the pacing pulse to the firstventricular site after expiration of an AV delay interval triggered byan atrial pace.
 4. The device of claim 1 wherein the controller isprogrammed to measure an intrinsic conduction delay between the firstand second ventricular sites during an intrinsic contraction, referredto as a V-V interval, and set the AV delay interval as a function of theV-V interval.
 5. The device of claim 4 wherein the controller isprogrammed to set the AV delay interval equal to a linear function ofthe V-V interval subtracted from a measured intrinsic AV delay interval.6. The device of claim 1 further comprising: an exertion level sensor;wherein the controller is programmed to measure the patient's exertionlevel with the exertion level sensor; and, wherein the controller isprogrammed to alternate between a pulse output sequence that pre-excitesthe first ventricular site and a pulse output sequence that does notpre-excite the first ventricular site in accordance with the exertionlevel measurement such that pre-excitation of the first ventricular siteis discontinued during periods of increased exertion.
 7. The device ofclaim 6 wherein the exertion level sensor is an accelerometer or minuteventilation sensor.
 8. The device of claim 6 wherein the controller isprogrammed to vary the AV delay interval dynamically with a measuredheart rate.
 9. The device of claim 6 wherein the controller isprogrammed to vary the AV delay interval dynamically with a measuredexertion level.
 10. The device of claim 1 wherein the controller isprogrammed to alternately switch between delivering paces to the firstventricular site in and the second pacing site during cardiac cycles.11. The device of claim 10 wherein the controller is programmed toswitch between delivering paces to the first ventricular site and thesecond ventricular site in accordance with an exertion levelmeasurement.
 12. The device of claim 1 wherein the controller isprogrammed to deliver pacing pulses to a plurality of pacing sites asdefined by a specified pulse output configuration and in accordance witha defined pulse output sequence such that the stressed first ventricularsite is excited before other regions of the ventricle.
 13. The device ofclaim 12 wherein the pulse output sequence specifies that the paces aredelivered after an AV delay interval following an atrial sense or pace.14. The device of claim 12 wherein the controller is programmed toadjust the pulse output sequence in accordance with measurements ofconduction delays that reflect regional variations in myocardial mass.15. The device of claim 12 wherein the controller is programmed toadjust the pulse output sequence in accordance with impedancemeasurements that reflect regional variations in myocardial mass. 16.The device of claim 12 wherein the controller is programmed to adjustthe pulse output sequence in accordance with impedance measurements thatreflect variations in contraction sequence.
 17. The device of claim 12wherein the controller is programmed to adjust the pulse output sequenceused to pre-excite the stressed region in accordance with detectedchanges in the remodeling process.
 18. A method for operating cardiacpacing device, comprising: connecting sensing and pulse generationcircuitry of the device to a first electrode disposed at a stressedfirst ventricular site, to a second electrode disposed at a secondventricular site that is excited earlier during an intrinsiccontraction; programming a device controller to deliver pacing pulses tothe first ventricular site during a cardiac cycle before excitation ofthe second ventricular site in order to subject the stressed region toless mechanical stress when the myocardium contracts.
 19. The method ofclaim 18 further comprising: connecting sensing and pulse generationcircuitry of the device to an atrial electrode; and, programming thecontroller to deliver pacing pulses to the first ventricular site afterexpiration of an AV delay interval triggered by an atrial sense or pace.20. The method of claim 19 further comprising measuring an intrinsicconduction delay between the first and second ventricular sites duringan intrinsic contraction, referred to as a V-V interval, and setting theAV delay interval as a function of the V-V interval.